Heterocyclic cytotoxic agents

ABSTRACT

The present invention provides compounds of formula I:                    
     wherein the R substituents and atoms X and Y are as defined in specification. The present invention also provides pharmaceutical compositions and methods of inhibiting cancer cell growth.

This is a 371 of PCT/US98/26292, filed Dec. 11, 1998 which is acontinuation of Ser. No. 08/989,576, filed Dec. 13, 1997, U.S. Pat. No.6,140,329.

GOVERNMENT FUNDING

The invention described herein was made with government support undergrant CA 39662 awarded by the National Cancer Institute. The UnitedStates Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

DNA-topoisomerases are enzymes which are present in the nuclei of cellswhere they catalyze the breaking and rejoining of DNA strands, whichcontrol the topological state of DNA. Recent studies also suggest thattopoisomerases are also involved in regulating template supercoilingduring RNA transcription. There are two major classes of mammaliantopoisomerases. DNA-topoisomerase-1 catalyzes changes in the topologicalstate of duplex DNA by performing transient single-strand breakage-unioncycles. In contrast, mammalian topoisomerase II alters the topology ofDNA by causing a transient enzyme bridged double-strand break, followedby strand passing and resealing. Mammalian topoisomerase II has beenfurther classified as Type II α and Type II β. The antitumor activityassociated with agents which are topoisomerase poisons is associatedwith their ability to stabilize the enzyme-DNA cleavable complex. Thisdrug-induced stabilization of the enzyme-DNA cleavable complexeffectively converts the enzyme into a cellular poison.

Several antitumor agents in clinical use have potent activity asmammalian topoisomerase II poisons. These include adriamycin,actinomycin D, daunomycin, VP-16, and VM-26 (teniposide orepipodophyllotoxin). In contrast to the number of clinical andexperimental drugs which act as topoisomerase II poisons, there arecurrently only a limited number of agents which have been identified astopoisomerase I poisons. Camptothecin and its structurally-relatedanalogs are among the most extensively studied topoisomerase I poisons.Recently, bi- and terbenzimidazoles (Chen et al., Cancer Res. 1993, 53,1332-1335; Sun et al., J. Med. Chem. 1995, 38, 3638-3644; Kim et al., J.Med. Chem. 1996, 39, 992-998), certain benzo[c]phenanthridine andprotoberberine alkaloids and their synthetic analogs (Makhey et al.,Med. Chem. Res. 1995, 5, 1-12; Janin et al., J. Med. Chem 1975, 18,708-713; Makhey et al., Bioorg. & Med. Chem. 1996, 4, 781-791), as wellas the fungal metabolites, bulgarein (Fujii et al., J. Biol. Chem. 1993,268, 13160-13165) and saintopin (Yamashita et al., Biochemistry 1991,30, 5838-5845) and indolocarbazoles (Yamashita et al., Biochemistry1992, 31, 12069-12075) have been identified as topoisomerase I poisons.

The exceptional topoisomerase poisoning observed with coralyne,nitidine, 5,6-dihydro-8-desmethylcoralyne and related analogs promptedseveral recent studies on those structural features which are associatedwith their ability to act specifically as poisons of topoisomerase I ortopoisomerase II (Gatto et al., Cancer Res. 1996, 56, 2795-2800; Wang etal., Chem. Res. Toxicol. 1996, 9, 75-83; Wang et al., Chem. Res.Toxicol., 1993, 6, 813-818). A common feature associated with all threeof these agents is the presence of a 3-phenylisoquinolinium moietywithin their structure.

Despite the observation that several of these compounds had similarpotency to camptothecin as a topoisomerase I poison or similar potencyto VM-26 as a topoisomerase II poison, they possessed only modestcytotoxic activity. The absence of a more direct correlation with theirpotency as topoisomerase poisons was attributed, in part, to thelikelihood that these agents are not likely to be absorbed aseffectively into cells as either camptothecin or VM-26. The presence ofthe quaternary ammonium group most likely impedes cellular uptake. Ithas been speculated that agents such as coralyne and nitidine may needto undergo hydrolysis to permit effective transport, with subsequentdehydration or cyclodehydration to reform the quaternary ammonium parentcompound. This may explain the relatively poor antitumor activityobserved in vivo with agents such as coralyne or nitidine.

Presently, a need exists for novel anti-cancer agents, for anti-canceragents that exhibit improved activity, and for anti-cancer agents thatexhibit fewer side-effects or improved selectivity compared to existingagents.

SUMMARY OF THE INVENTION

The present invention provides compounds that show inhibitory activityagainst topoisomerase I and/or topoisomerase II, and compounds that areeffective cytotoxic agents against cancer cells, includingdrug-resistant cancer cells. Accordingly, the invention provides acompound of the invention which is a compound of formula I:

wherein

R₁, R₂, and R₃ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₁ and R₂ taken together are methylenedioxy and R₃is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₂ and R₃ takentogether are methylenedioxy and R₁ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo;

R₄ is oxy, (C₁-C₆)alkyl, or is absent;

R₅ is hydrogen, hydroxy, or (C₁-C₆)alkyl;

R₆, R₇ and R₈ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₆ and R₇ taken together are methylenedioxy and R₈is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₇ and R₈ takentogether are methylenedioxy and R₆ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h),C(═O)R_(k), COOR_(k), OR_(m), or halo;

each bond represented by ————— is individually present or absent;

X is C(R_(a))(R_(b)) or NR_(c);

Y is C(R_(d))(R_(e)) or NR_(f);

if present, R_(a) and R_(b) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(a) is hydrogen or (C₁-C₆)alkyl and R_(b) isabsent if the bond between the 11- and 12-positions represented by —————is present;

if present, R_(c) and R_(f) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(c) and R_(f) are each independently (C₁-C₆)alkylor absent if the bond between the 11- and 12-positions represented by————— is present;

if present, R_(d) and R_(e) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(d) is hydrogen or (C₁-C₆)alkyl and R_(e) isabsent if the bond between the 11- and 12-positions represented by —————is present;

each R_(g) and R_(h) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, aryl,aryl(C₁-C₆)alkyl, aryloxy, or aryl(C₁-C₆)alkoxy; or R_(g) and R_(h)together with the nitrogen to which they are attached are pyrrolidino,piperidino, morpholino, or thiomorpholino;

each R_(k) is independently hydrogen, or (C₁-C₆)alkyl; and

each R_(m) is independently (C₁-C₆)alkanoyl, aryl, or aryl(C₁-C₆)alkyl;

wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or (C₁-C₆)alkoxy of R¹, R²,R³, R⁶, R⁷, R⁸, or R_(k) is optionally substituted on carbon with 1, 2,or 3 substituents independently selected from hydroxy, halo,NR_(n)R_(p), (C₃-C₆)cycloalkyl, or (C₁-C₆)alkoxy; wherein each R_(n) andR_(p) is independently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkoxy, or (C₁-C₆)alkanoyl; or R_(n) and R_(p) together with thenitrogen to which they are attached are pyrrolidino, piperidino,morpholino, or thiomorpholino;

wherein any aryl is optionally be substituted with 1, 2, or 3substituents independently selected from hydroxy, halo, nitro,trifluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, and (C₁-C₆)alkoxy;

provided that at least one of R₂ and R₈ is hydrogen, methyl, nitro,hydroxy, amino, fluoro or chloro; or at least one of R₂ and R₈ formspart of a methylenedioxy; and

provided that R₁-R₃ and R₆-R₈ are not all hydrogen;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising aeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

The invention also provides a method of inhibiting cancer cell growth,comprising administering to a mammal afflicted with cancer, an amount ofa compound of formula (I), effective to inhibit the growth of saidcancer cells.

The invention also provides a method comprising inhibiting cancer cellgrowth by contacting said cancer cell in vitro or in vivo with an amountof a compound of claim 1, effective to inhibit the growth of said cancercell.

The invention also provides a compound of formula I for use in medicaltherapy (preferably for use in treating cancer, e.g. solid tumors), aswell as the use of a compound of formula I for the manufacture of amedicament useful for the treatment of cancer, e.g. solid tumors.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of formula I are useful to prepare other compounds offormula I.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the structure of representative compounds of theinvention(6, 7, 27, 28) and other compounds (4 and 5).

FIG. 2 Illustrates the synthesis of compounds of the invention.

FIG. 3 Illustrates the synthesis of compounds of the invention.

FIG. 4 Illustrates the synthesis of intermediate compound 9.

FIG. 5 Illustrates the synthesis of intermediate compound 22.

FIG. 6 Illustrates the synthesis of compounds of the invention wherein Xis CR_(a) and Y is CR_(d).

FIG. 7 Illustrates the synthesis of compounds of the invention wherein Xis CR_(a), Y is CR_(d), and R₅ is alkyl.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine topoisomerase poisioning activityor cytotoxicity using the standard tests described herein, or usingother similar tests which are well known in the art.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;(C₁-C₆)alkanoyl can be acetyl, propanoyl, butanoyl, pentanoyl, orhexanoyl; and aryl can be phenyl, indenyl, or naphthyl;.

Specifically, R₂ or R₇ can be hydroxy, methoxy, benzyloxy, amino,hydroxymethyl, aminomethyl, aminocarbonyl, methoxycarbonyl,trifluoromethyl, 3-aminopropoxycarbonyl, or 2-hydroxyethyl.

Specifically, R₃ can be hydrogen.

Specifically, R₄ can be absent; or R₄ can be (C₁-C₆)alkyl.

Specifically, R₅ can be methyl or hydrogen.

A specific group of compounds are compounds of formula I wherein R₁, R₂and R₃ are each individually hydrogen, or (C₁-C₆)alkoxy; or R₁ and R₂taken together are methylenedioxy (—OCH₂O—) and R₃ is hydrogen or(C₁-C₆))alkoxy; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I wherein:R₁, R₂ and R₃ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₁ and R₂ taken together are methylenedioxy and R₃is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₂ and R₃ takentogether are methylenedioxy and R₁ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; R₄ is oxy, (C₁-C₆)alkyl, or is absent; R₅ is hydrogen,hydroxy, or (C₁-C₆)alkyl; R₆, R₇ and R₈ are each individually hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy,NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₆ and R₇ taken together aremethylenedioxy and R₈ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo;or R₇ and R₈ taken together are methylenedioxy and R₆ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy,NR_(g)R_(h), COOR_(k), OR_(m), or halo; each bond represented by —————is individually present or absent; X is C(R_(a))(R_(b)) or NR_(c); Y isC(R_(d))(R_(e)) or NR_(f); if present, R_(a) and R_(b) are eachindependently hydrogen or (C₁-C₆)alkyl if the bond between the 11- and12-positions represented by ————— is absent; or R_(a) is hydrogen or(C₁-C₆)alkyl and R_(b) is absent if the bond between the 1- and12-positions represented by ————— is present; if present, R_(a) andR_(f) are each independently hydrogen or (C₁-C₆)alkyl if the bondbetween the 11- and 12-positions represented by ————— is absent; orR_(a) and R_(f) are each independently (C₁-C₆)alkyl or absent if thebond between the 11- and 12-positions represented by ————— is present;if present, R_(d) and R_(e) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(d) is hydrogen or (C₁-C₆)alkyl and R_(c) isabsent if the bond between the 11- and 12-positions represented by —————is present; each R_(g) and R_(h) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, aryl,aryl(C₁-C₆)alkyl, aryloxy, or aryl(C₁-C₆)alkoxy; or R_(g) and R_(h)together with the nitrogen to which they are attached are pyrrolidino,piperidino, morpholino, or thiomorpholino; each R_(k) is independentlyhydrogen, or (C₁-C₆)alkyl; and each R_(m) is independently(C₁-C₆)alkanoyl, aryl, or aryl(C₁-C₆))alkyl; provided that at least oneof R₂ and R₈ is hydrogen, methyl, nitro, hydroxy, amino, fluoro orchloro; or at least one of R₂ and R₈ forms part of a methylenedioxy; andprovided that R₁-R₃ and R₆-R₈ are not all hydrogen; or apharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinR₇ or R₈ is (C₁-C₆)alkoxy; or R₇ and R₈ taken together aremethylenedioxy; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinR₇ and R₈ taken together are methylenedioxy; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinthe bonds represented by ————— are both present; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinthe bond between the 5- and the 6-positions that is represented by —————is absent; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinthe bond between the 11- and the 12-positions that is represented by————— is absent; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinthe bonds represented by ————— are both absent; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds are compounds of formula I wherein Xis NR_(c); Y is NR_(f); and R_(c) and R_(f) are each hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(c) and R_(f) are each (C₁-C₆)alkyl or absent ifthe bond between the 11- and 12-positions represented by ————— ispresent; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds of formula I, are compounds offormula III:

wherein

R₁-R₈ are defined as hereinabove for the corresponding radical in acompound of formula I; each bond represented by ————— is individuallypresent or absent; and R_(f) is hydrogen or (C₁-C₆)alkyl if the bondbetween the 11- and 12-positions represented by ————— is absent; orR_(f) is (C₁-C₆)alkyl or absent if the bond between the 11- and12-positions represented by ————— is present; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds of formula I, are compounds offormula IV:

wherein R₁-R₈ are defined as hereinabove for the corresponding radicalin a compound of formula I; each bond represented by ————— isindividually present or absent; and R_(c) is hydrogen or (C₁-C₆)alkyl ifthe bond between the 11- and 12-positions represented by ————— isabsent; or R_(c) is (C₁-C₆)alkyl or absent if the bond between the 11-and 12-positions represented by ————— is present; or a pharmaceuticallyacceptable salt thereof

Another specific group of compounds are compounds of formula I whereinR₁ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₁ and R₂ takentogether are methylenedioxy; or a pharmaceutically acceptable saltthereof.

Another specific group of compounds are compounds of formula I whereinR₂ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinR₃ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₂ and R₃ takentogether are methylenedioxy; or a pharmaceutically acceptable saltthereof.

Another specific group of compounds are compounds of formula I whereinR₈ is (C₁-C₆)alkoxy, nitro, hydroxy or halo; or R₇ and R₈ taken togetherare methylenedioxy; or a pharmaceutically acceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinR₇ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or a pharmaceuticallyacceptable salt thereof.

Another specific group of compounds are compounds of formula I whereinR₆ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₆ and R₇ takentogether are methylenedioxy; or a pharmaceutically acceptable saltthereof.

A preferred compound of the invention is a compound of formula I:

wherein

R₆ R₂ and R₃ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₁ and R₂taken together are methylenedioxy (—OCH₂O—) and R₃ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, or halo;or R₂ and R₃ taken together are methylenedioxy (—OCH₂O—) and R₁ ishydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxyor halo;

R₄ is oxy (forming an amine oxide), (C₁-C₆)alkyl, or is absent;

R₅ is hydrogen, hydroxy, or (C₁-C₆)alkyl;

R₆, R₇ and R₈ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₆ and R₇taken together are methylenedioxy (—OCH₂O—) and R₈ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, or halo;or R₇ and R₈ taken together are methylenedioxy (—OCH₂O—) and R₆ ishydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxyor halo;

each bond represented by ————— is individually present or absent;

X is C(R_(a))(R_(b)) or NR_(c);

Y is C(R_(d))(R_(e)) or NR_(f);

if present, R_(a) and R_(b) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(a) is hydrogen or (C₁-C₆)alkyl and R_(b) isabsent if the bond between the 11- and 12-positions represented by —————is present;

if present, R_(c) and R_(f) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(c) and R_(f) are each independently (C₁-C₆)alkylor absent if the bond between the 11- and 12-positions represented by————— is present; and

if present, R_(d) and R_(e) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(d) is hydrogen or (C₁-C₆)alkyl and R_(e) isabsent if the bond between the 11- and 12-positions represented by —————is present;

provided that R₂ and R₈ are not both (C₁-C₆)alkoxy; and

provided that R₁-R₃ and R₆-R₈ are not all hydrogen;

or a pharmaceutically acceptable salt thereof.

Another preferred compound of formula (I) is a compounds of formula (V):

wherein

R₁-R₈ are defined as hereinabove for the corresponding radical in acompound of formula I; each bond represented by ————— is individuallypresent or absent; or a pharmaceutically acceptable salt thereof.

A preferred compound of the invention is2,3-methylenedioxy-8,9-dimethoxybenzo[i]phenanthridine; or apharmaceutically acceptable salt thereof.

A compound of formula I can be prepared by reducing the nitro group of acompound of formula II:

wherein R₁-R₃, R₆-R₈, X and Y are defined as they are for a compound offormula I, under conditions which give the imine ring closure product.Conditions suitable for reduction of the nitro group are well known tothe art. For example, the hydrolysis may conveniently be carried outwith zinc in acetic acid, under conditions similar to those described inExample 1.

An intermediate useful for preparing a compound of formula I, is acompound of formula II. A compound of formula II (for example compound17 or 18) can be prepared using procedures similar to those illustratedin FIG. 2 and described in the sub-parts of Examples 1 and 3. Treatmentof 6,7-dimethoxy-β-tetralone (8) and 6,7-methylenedioxy-β-tetralone (9)with dimethyl formamide and phosphorus tribromide gave the respective3,4-dihydro-2-bromonapthaldehyde derivatives in about 70% yield, whichwere oxidized using DDQ in toluene quantitatively to the respectivebromonapthaldehydes, 10 and 11. Acetals 12 and 13 were obtained in 95%yield by treatment of the respective bromonaphthaldehydes with ethyleneglycol in presence of a catalytic amount of p-toluenesulfonic acid. ADean-Stark apparatus was used to remove the water generated during thereaction. Lithium-halogen exchange was performed by treatment of theacetals 12 and 13 with butyllithium and then quenched withtrimethylborate. Acidic work-up of the reaction products resulted in theformation of the boronic acid derivatives, 14 and 15 respectively.Palladium (0) catalyzed coupling of compounds 14 and 15 with theo-bromonitrobenzene derivative, 16, resulted in the formation of the2-phenylnapthalene derivatives, 17 and 18, respectively, in about 80%yield. Reduction and concomitant cyclization of the nitro groups of 17and 18 resulted in the of the desired benzo[i]phenanthridines, 4 and 6,respectively, in about 70% yield.

A compound of formula II (for example compound 25 or 26) can also beprepared using procedures similar to those illustrated in FIG. 3 anddescribed in the sub-parts of Examples 2 and 4. Grignard reactionsperformed on the respective naphthaldehydes, 10 and 11, withmethylmagnesium bromide, followed by oxidation of the alcohols obtainedwith pyridinium chlorochromate resulted in the formation of the ketones23 and 24, respectively. These ketones were then directly coupled withthe tin compound (22) to give the 2-phenylnapthalenes 25 and 26,respectively. Reduction and concomitant cyclization of 25 and 26occurred on treatment with zinc in acetic acid to give the desired5-methyl substituted benzo[i]phenanthridines 5 and 7, respectively.

Another intermediate useful for preparing compounds of the invention isthe β-tetralone 9, which can be prepared as illustrated in FIG. 4.3,4-methylenedioxy-phenylpropionic acid was esterified to give ethylester, 19. Treatment of 19 with the anion of dimethyl sulfate resultedin the formation of the β-ketosulfoxide, 20, which cyclized on treatmentwith trifluoroacetic acid to the 1-methylthio-β-tetralone, 21. Reductivedesulfurization of 21 gave 6,7-methylenedioxy-β-tetralone, 9.

Another intermediate useful for preparing compounds of the invention isthe compound 22, which can be prepared as illustrated in FIG. 5.Nitration of 4-bromo-1,2-dimethoxybenzene gave compound 16, which wastreated with hexamethylditin to give the tin compound 22.

As illustrated in FIG. 6, a compound of formula (I) wherein X is CR_(a)and Y is CR_(d) can be prepared using procedures similar to thosedescribed herein.

As illustrated in FIG. 7, a compound of formula (I) wherein X is CR_(a),Y is CR_(d), and R₅ is alkyl can be prepared using procedures similar tothose described herein.

A compound of formula (I) wherein X and/or Y is nitrogen can be preparedusing techniques similar to those described by: M. J. S. Dewar and W. H.Poesche, A New Route to Polycyclic Benzocinnolines, J. Chem. Soc.,2201-2203, 1963; R. S. W. Braithwaite and G. K. Robinson, UnsymmetricalPolynuclear Cinnoline Derivatives. Part I. Cyclisation of SomeCyclohexane-1,2-dione 1-Arylhydrazones, J. Chem. Soc., 3671-3676, 1962;J. F. Corbett abd P. F. Holt, Polycyclic Cinnoline Derivatives. PartViii. Cinnolines and their N-oxides and oo′-Diaminobiaryls, J. Chem.Soc., 3695-3699, 1961.

The formation of quaternary N-methylated analogs ofbenzo[i]phenathridines can be accomplished by heating the compound neatin the presence of dimethyl sulfate in a sealed tube as described by A.R. Surrey, Org. Syn., Coll. Vol., 3, 753-756, 1955 in the preparation ofPyrocyanine, see below.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and αglycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureis form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of formula I in a liquidcomposition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound may conveniently be administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The ability of a compound of the invention to effect topoisomerase I orII mediated DNA cleavage can be determined using pharmacological modelsthat are well known to the art, for example, using a model like Test Adescribed below.

Test A

Topoisomerase I and Topoisomerase II Cleavage Assay

Representative compounds of the invention were evaluated in cleavageassays for the recombinant topoisomerases I and calf thymustopoisomerases I and II. These assays were preformed as described by B.Gatto et al. Cancer Res., 1996, 56, 2795-2800. Human topoisomerase I wasisolated as a recombinant fusion protein using a T7 expression system.DNA topoisomerase II was purified from calf thymus gland as reported byHalligan, B. D.; Edwards, K. A.; Liu, L. F. “Purification andcharacterization of a type II DNA topoisomerase from bovine calfthymus,” J. Biol. Chem. 1985, 260, 2475. Plasmid YEpG was purified bythe alkali lysis method followed by phenol deproteination andCsCl/ethidium isopycnic centrifugation as described by Maniatis, T.;Fritsch, E. F.; Sambrook, J. Molecular Cloning, a Laboratory Manual;Cold Spring Harbor Laboratory: Cold Spring Harbor, N.Y. 1982; pp149-185. The end-labeling of the plasmid was accomplished by digestionwith a restriction enzyme followed by end-filling with Klenow polymeraseas previously described by Liu, L. F.; Rowe, T. C.; Yang, L.; Tewey, K.M.; Chen, G. L. “Cleavage of DNA by mammalian topoisomerase II,” J.Biol. Chem. 1983, 258, 15365.

The cytotoxic effects of a compound of the invention can be determinedusing pharmacological models that are well known to the art, forexample, using a model like Test B described below.

Test B

Cytotoxicity Assay

The cytotoxicity was determined using the MTT-microtiter platetetrazolinium cytotoxicity assay (MTA) (See Chen A. Y. et al. CancerRes. 1993, 53, 1332; Mosmann, T. J., J. Immunol. Methods 1983, 65, 55;and Carmichael, J. et al. Cancer Res. 1987, 47, 936). The humanlymphoblast RPMI 8402 and its camptothecin-resistant variant cell line,CPT-K5 were provided by Dr. Toshiwo Andoh (Aichi Cancer Center ResearchInstitute, Nagoya, Japan) (see Andoh, T.; Okada, K. “Drug resistancemechanisms of topoisomerase I drugs,” Adv. in Pharmacology 1994, 29B,93. The cytotoxicity assay was performed using 96-well microtiterplates. Cells were grown in suspension at 37° C. in 5% CO₂ andmaintained by regular passage in RPMI medium supplemented with 10%heat-inactivated fetal bovine serum, L-glutamine (2 mM), penicillin (100U/mL), and streptomycin (0.1 mg/mL). For determination of IC₅₀, cellswere exposed continuously with varying concentrations of drug and MTTassays were performed at the end of the fourth day.

TABLE 1 Pharmacological Activity of Compounds of the Invention Topo TopoCytotoxicity IC₅₀ ^(a) (μM) I-mediated II-mediated Cell Lines CompoundDNA cleavage^(b) DNA cleavage^(c) RPMI CPT-K5  4 >1000 >1000 22.9 22.9 5 >1000 >1000 27.5 >27.5^(d)  6 100 10 7.5 7.0  7 200 100 10.1 14.4 2725 >1000 1.3 5.2 28 25 >1000 0.2 0.2 29 100 >1000 15 20 30 250 >1000 7.57.5 31 50 >1000 3.0 3.0 Nitidine 1 1 0.65 >2.6^(d) CPT 1 >1000 0.004>10^(d) VM-26 >1000 1 0.3 0.5 ^(a)IC₅₀ has been calculated after 4 daysof continuous drug exposure. ^(b)Topoisomerase I cleavage values arereported as REC, Relative Effective Concentration, i.e., concentrationsrelative to camptothecin (CPT), whose value is arbitrarily assumed as 1,that are able to produce the same cleavage on the plasmid DNA in thepresence of human topoisomerase I. ^(c)Topoisomerase II cleavage valuesare reported as REC, Relative Effective Concentration, i.e.,concentrations relative to VM-26, whose value is arbitrarily assumed as1, that are able to produce the same cleavage on the plasmid DNA in thepresence of calf thymus topoisomerase II. VM-26 (teniposide orepipodophyllotoxin) was obtained from the National Cancer Institute.^(d)IC₅₀ value substantially greater than the highest doses assayed

Certain compounds of formula I, are potent topoisomerase I poisons.Additionally, compounds of formula I generally possess cytotoxicactivity against RPMI 8402 cancer cells and camptothecin resistantCPT-K5 cells. Accordingly, compounds of formula I may be useful ascytotoxic agents, for the treatment of cancers, in particular, solidmammalian tumors or hematologic malignancies. Additionally, compounds ofthe invention may be useful as pharmacological tools for the furtherinvestigation of topoisomerase function.

As used herein, the term “solid mammalian tumors” include cancers of thehead and neck, lung, mesothelioma, mediastinum, esophagus, stomach,pancreas, hepatobiliary system, small intestine, colon, rectum, anus,kidney, ureter, bladder, prostate, urethra, penis, testis, gynecologicalorgans, ovarian, breast, endocrine system, skin central nervous system;sarcomas of the soft tissue and bone; and melanoma of cutaneous andintraocular origin. The term “hematological malignancies” includeschildhood leukemia and lymphomas, Hodgkin's disease, lymphomas oflymphocytic and cutaneous origin, acute and chronic leukemia, plasmacell neoplasm and cancers associated with AIDS. The preferred mammalianspecies for treatment are humans and domesticated animals.

Compounds 6 and 7 exhibit potent activity as topoisomerase I poisions.This is believed to be due in part to the favorable placement of themethylenedioxy group. Compounds 4 and 5 demonstrate significantly lesstopoisomerase I poisioning activity. This is believed to be due to thepresence of methoxy group at the (R₈) 3-position. Based on thisreasoning, it might be expected that compound 28 would also possessdiminished topoisomerase I poisioning activity, in view of the fact thatthere is a methoxy group at the 3-position. Compound 28, however,demonstrates potent topoisomerase poisioning activity.

This apparent anomaly can be explained by the fact that, if compound 28(as shown in FIG. 1) is flipped vertically by 180 degrees, and thenflipped horizontally by 180 degrees, it provides the followingstructure.

This structure has a methylenedioxy substituent in the positionscorresponding to R₇ and R₈ in a compound of formula I. This suggeststhat benzo[i]phenanthridines having alkoxy substituents at either the 3-or 9-position should retain good topoisomerase poisioning activity,whereas those compounds having alkoxy substituents at both the 3- and9-position may possess diminished activity. This also suggests thatcompounds having a nitrogen in the 12-position should retaintopoisomerase poisioning activity.

The invention will now be illustrated by the following non-limitingExamples, wherein unless otherwise stated: melting points weredetermined with a Thomas-Hoover Unimelt capillary melting pointapparatus; column chromatography refers to, flash chromatographyconducted on SiliTech 32-63 μm, (ICN Biomedicals, Eschwegge, Ger.) usingthe solvent systems indicated; infrared spectral data (IR) were obtainedon a Perkin-Elmer 1600 Fourier transform spectrophotometer and arereported in cm⁻¹; proton (¹H NMR) and carbon (¹³C NMR) nuclear magneticresonance were recorded on a Varian Gemini-200 Fourier Transformspectrometer; NMR spectra (200 MHz ¹H and 50 MHz ¹³C) were recorded inthe deuterated solvent indicated with chemical shifts reported in δunits downfield from tetramethylsilane (TMS); coupling constants arereported in hertz (Hz); mass spectra were obtained from WashingtonUniversity Resource for Biomedical and Bio-organic Mass Spectrometrywithin the Department of Chemistry at Washington University, St. Louis,Mo.; and combustion analyses were performed by Atlantic Microlabs, Inc.,Norcross, Ga., and were within ±0.4% of the theoretical value.

EXAMPLES Example 1 2,3,8,9-Tetramethoxybenzo[i]phenanthridine (4)

Compound 17 (100 mg, 0.52 mmol) was dissolved in glacial acetic acid (8mL) and heated to reflux with zinc dust (200 mg, 3.2 mmol) for 4 hours.The acetic acid was evaporated in vacuo, and the residue was extractedwith chloroform. The chloroform solution was filtered through a celitebed. The filtrate was washed successively with saturated sodiumbicarbonate solution and brine and evaporated to dryness. The residuewas purified by chromatography (silica), with hexanes:ethyl acetate(1:1) as the eluent to give the title compound in 54% yield; mp=267-268°C.; IR (Nujol) 1621, 1513, 1982; ¹H NMR δ4.04 (3H, s), 4.06 (3H, s),4.10 (3H, s), 4.13 (3H, s), 7.22 (1H, s), 7.55 (1H, s), 7.74 (1H, s),7.89 (1H, d, J=8.8), 8.05 (1H, s), 8.18 (1H, d, J=8.8), 9.82 (1H, s);¹³C NMR δ56.4, 56.6, 102.0, 102.3, 108.5, 109.9, 118.3, 118.4, 120.7,120.8, 125.7, 127.5, 130.7, 141.5, 145.9, 150.0, 150.1, 150.9, 151.4;HRMS calcd for C₂₁H₁₉NO₄: 349.1314; found: 349.1321.

The intermediate compound 17 was prepared as follows.

a. 2-Bromo-6,7-dimethoxy-1-napthaldehyde (10)

Dimethylformamide (3.0 g, 41 mmol) was added dropwise to solution ofphosphorus tribromide (3.3 mL, 35 mmol) in dry chloroform (50 mL) at 0°C. The mixture was stirred at 0° C. for 1 h to give pale yellowsuspension. A solution of compound 8 (2.0 g, 9.7 mmol) in chloroform wasadded to the yellow suspension and the mixture was heated at reflux for1 h. The reaction mixture was cooled to 0° C. and saturated aqueousNaHCO₃ solution was added dropwise until no effervescence was obtained.The resulting mixture was extracted with dichloromethane, dried (Na₂SO₄)and evaporated to provide the respective2-bromo-3,4-dihydro-1-napthaldehyde derivatives as yellow solids. Eachof the 2-bromo-3,4-dihydro-1-napthaldehyde derivatives werechromatographed on silica gel using a 3:1 mixture of hexanes:ethylacetate as the eluent to give the 2-bromo-3,4-dihydro-1-napthaldehydesin an 87% yield. The 2-bromo-3,4-dihydro-1-naphthaldehyde (2.4 g, 8.1mmol) and DDQ (2.2 g, 97 mmol) was refluxed in toluene (50 mL) for 15 h.After cooling to room temperature, the mixture was subjected tofiltration through a celite bed and the filtrate was evaporated todryness. The residue obtained was chromatographed on 75 g silica gelusing a 3:1 mixture of hexanes:ethyl acetate as eluent to give the2-bromo-1-napthaldehyde in a 95% yield; ¹H NMR δ4.00 (3H, s), 4.05 (3H,s), 7.07 (1H, s), 7.54 (1H, d, J=8.5), 7.79 (1H, d, J=8.5), 8.71 (1H,s), 10.74 (1H, s); ¹³C NMR δ56.3, 56.6, 104.2, 107.0, 126.5, 128.8,129.4, 129.8, 129.9, 134.3, 150.4, 153.1, 195.9; HRMS calcd forC₁₃H₁₁O₃Br: 293.9891; found: 293.9896.

b. 2-Bromo-6,7-dimethoxynapthaldehyde-1-ethylacetal (12)

Compound 10 (540 mg, 1.95 mmol), ethylene glycol (0.7 mL) andp-toluenesulfonic acid (10 mg) were dissolved in 30 mL dry toluene. Thisreaction mixture refluxed under nitrogen in a flask fitted with aDean-Stark apparatus to remove the water formed during acetal formation.At the end of the reaction (15 h), the solvent from the cooled reactionmixture was evaporated in vacuo and the residue obtained was dissolvedin 50 mL ethyl acetate. The ethyl acetate solution was washed with asaturated solution of sodium bicarbonate, dried and the solvent wasremoved to give the crude acetal. Chromatography on silica gel using a3:17 mixture of ethyl acetate:hexanes afforded the pure acetal as aclear viscous liquid in a 95% yield; IR (Nujol) 1660, 1635; ¹H NMR δ4.02(3H, s), 4.06 (3H, s), 4.13-4.19 (2H, m), 4.38-4.48(2H, m), 7.09 (1H,s), 7.54-7.68 (2H, m), 7.72 (1H, s), 7.78 (1H, s); ¹³C NMR δ56.2, 56.6,65.7, 102.8, 104.6, 106.5, 122.9, 128.4, 129.1, 130.5, 131.2, 131.3,148.0, 148.5; Anal. calcd for C₁₅H₁₅O₄Br: C, 53.11; H, 4.48; Found: C,52.93; H, 4.51.

c. 1-Formyl-6,7-dimethoxynaphth-2-yl boronic acid (14)

Acetal 12 (1.4 mmol) was dissolved in 10 mL anhydrous tetrahydrofuran.This solution was stirred under nitrogen at −78 ° C. A hexanes solutionof n-butyllithium (1.2 mL, 2.8 mmol) was added slowly and the reactionmixture was stirred at −78 ° C. for 30 min. A pale yellowish brownsolution was obtained. To this yellow reaction mixture trimethylborate(0.5 mL, 4.2 mmol) was added and the resulting mixture was stirred at−78 ° C. for 1 h prior to allowing it to come to room temperature. A 5%solution of hydrochloric acid (20 mL) was added to the reaction mixtureand stirred for 30 min at room temperature. The tetrahydrofuran wasevaporated in vacuo and the water layer was extracted withdichloromethane. The combined organic layer was washed once with brine,dried and evaporated to give the boronic acid derivative 14, which wasused in the subsequent step without further purification.

d. 2-(3,4-Dimethoxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (17)

In a 3 neck flask compound 16 (876 mg, 3.34 mmol, prepared in sub-part ebelow) was taken with 430 mg of tetrakis(triphenylphosphine)palladium(0) in 20 mL dimethoxyethane and the resulting solution was stirred atroom temperature under nitrogen for 30 min. The solution changed colorfrom brown to yellow. A solution of compound 14 (1.1 mmol) in 5 mLdimethoxyethane was added to the reaction mixture followed by theaddition of 5 mL of 2 M sodium carbonate solution. The reaction mixturewas refluxed for 18 h. The reaction mixture was allowed to come to roomtemperature and the reaction mixture was filtered through a celite bed.The filtrate was evaporated to dryness and the residue obtained wascolumn chromatographed on 75 g silica gel using 1:9 mixture of ethylacetate:hexanes. The fourth compound eluting from the column wascollected and the combined fractions were evaporated in vacuo to givethe 2-phenyl-1-napthaldehyde derivative 17 in 22% yield, based on theacetal; mp=228-230; IR (Nujol) 1676, 1513, 1259. This compound was usedfor the synthesis of compound 4 without further characterization.

The intermediate compound 16 used in Example 1, sub-part d, was preparedas follows.

e. 3,4-Dimethoxy-6-nitro-bromobenzene (16)

3,4-Dimethoxybromobenzene (5 g, 23 mmol) was slowly added to a stirredsolution of 35 mL concentrated nitric acid and 105 mL glacial aceticacid maintained at 10° C. The reaction mixture was stirred at 15° C. for1 h and then diluted with 200 mL ice cold water. The resulting mixturewas extracted thrice with 200 mL portions of ether. The combined organicphase was dried and evaporated in vacuo. The crude product wasrecrystallized from ethanol to give bright yellow needle shaped crystalsof compound 16 in 92% yield; mp=122-124 ° C.; IR (Nujol) 1510, 1312; ¹HNMR δ3.94 (3H, s), 3.97 (3H, s), 7.12 (1H, s), 7.57 (1H, s); ¹³C NMRδ56.9, 57.2, 108.0, 109.5, 117.0, 148.7, 153.3; Anal. calcd forC₈H₈NO₄Br: C, 36.72; H, 3.14; N, 5.30; Found: C, 36.70; H, 3.13; N,5.29.

Example 2 5-Methyl-2,3,8,9-tetramethoxybenzo[i]phenanthridine (5)

Using a procedure similar to that described in Example 1, exceptreplacing the compound 17 used therein with compound 25, the titlecompound was prepared in 60% yield; mp=255-257 ° C.; IR (Nujol) 1620,1513, 1209; ¹H NMR δ3.42 (3H, s), 4.08 (6H, s), 4.13 (6H, s), 7.33 (1H,s), 7.52 (1H, s), 7.82 (1H, s), 7.98 (1H, d, J=8.8), 8.32 (1H, s), 8.35(1H, d,J=8.8); ¹³C NMR δ31.6, 56.4, 56.5, 56.6, 102.1, 108.7, 108.8,108.9, 118.6, 119.0, 122.2, 126.5, 129.0, 130.9, 132.6, 140.4, 149.1,149.6, 149.7, 151.7, 154.9; HRMS calcd for C₂₂H₂₁NO₄: 363.1470; found:363.1471.

The intermediate compound 25 was prepared as follows.

a. 1-Aceto-2-bromo-6,7-dimethoxynapthalene (23)

A 1.4 M solution of methylmagnesium bromide in tetrahydrofuran (16.8 mL,16.8 mmol) was added to a solution of napthaldehyde 10 in 20 mL drytetrahydrofuran at 0° C. under nitrogen. The reaction mixture wasstirred for 1 h at 0° C. The reaction was quenched by dropwise additionof 100 mL water followed by rapid addition of 50 mL 0.1 N hydrochloricacid. The reaction mixture was extracted with ethyl acetate, dried andthe solvent was evaporated in vacuo to give an oily residue. The oil wastriturated with chloroform to give the alcohol as a white needle shapedcrystalline solid in 95% yield. Pyridinium chlorochromate (857 mg, 3.98mmol) was suspended in 10 mL dry dichloromethane. The alcohols (2.49mmol) was added to this suspension and the resulting mixture was stirredunder nitrogen at room temperature for 6 h. Ether (100 mL) was added tothe reaction mixture and the suspension obtained was filtered through acelite bed. The filtrate was evaporated to dryness and the residueobtained was chromatographed on 75 g silica gel using a 1:9 mixture ofethyl acetate:hexanes to give the 1-aceto-2-bromonapthalene derivatives23 as fluffy bright white needles in 85% yield; mp=102-103° C.; IR(Nujol) 1693; ¹H NMR δ2.70 (3H, s), 3.95 (3H, s), 3.99 (3H, s), 6.84(1H, s), 7.10 (1H, s), 7.43 (1H, d, J=8.4), 7.56 (1H, d, J=8.4); ¹³C NMRδ32.4, 56.4, 103.1, 107.2, 113.3, 126.3, 128.2, 128.7, 129.1, 139.0,150.4, 151.4, 205.5; HRMS calcd for C₁₄H₁₃O₃Br: 308.0048; found:308.0059.

b. 1-Aceto-2-(3,4-dimethoxy-6-nitrophenyl)-6,7-dimethoxynapthalene (25)

A mixture containing compound 22 (0.98 mmol), the1-aceto-2-bromonapthalene 23 (0.89 mmol), (Ph₃P)₄Pd (106 mg) and coppercyanide (17 mg) was refluxed in 20 mL toluene under nitrogen for 20-24h. After cooling to room temperature, ethyl acetate (20 mL) was added tothe reaction mixture and the organic layer was poured into a separatingfunnel. The organic layer was washed with 20 mL of distilled water. Thetwo phases were allowed to separate as much as possible and the aqueouslayer was discarded. The remaining emulsion was passed through a celitebed. The organic layer was separated from the filtrate and evaporated todryness. The residue obtained was chromatographed on 75 g silica gelusing a 3:2 mixture of hexanes:ethyl acetate to give the1-aceto-2-(3,4-dimethoxy-6-nitrophenyl)naphthalene derivative 25 in 30%yield; mp=185-187° C.; IR (Nujol) 1689, 1503, 1260; ¹H NMR δ2.25 (3H,s), 3.90 (3H, s), 3.98 (3H, s), 4.02 (3H, s), 4.03 (3H, s), 6.76 (1H, s)(1H, d, J=8.4), 7.12 (1H, s), 7.18 (1H, s), 7.70 (I H, s), 7.71 (1H, d,J=8.4); ¹³C NMR δ32.7, 56.4, 56.9, 57.0, 57.1, 103.8, 107.2, 108.5,115.7, 124.9, 125.1, 128.2, 129.5, 130.1, 131.6, 136.9, 141.1, 149.0,150.5, 151.2, 152.8, 208.0; HRMS calcd for C₂₁H₁₉NO₇—C₂H₃O: 368.1134;found: 368.1135.

The intermediate compound 22 used in sub-part b was prepared as follows.

c. 3,4-Dimethoxy-6-nitrophenyl-trimethylstannane (22)

A mixture of hexamethylditin (2.0 g, 6.1 mmol), compound 16 (1.56 g, 6.0mmol) and Pd(PPh₃)₄ (163 mg, 0.14 mmol) in toluene (50 mL) was heated toreflux under nitrogen for 10 h. After cooling, 7 M KF aqueous solution(1 mL) was added with vigorous stirring. The mixture was passed though acelite bed and the filtrate was evaporated to dryness. The residue waschromatographed on 75 g silica gel using hexanes:ethyl acetate (5:1) aseluent. The relevant fractions were pooled and evaporated in vacuo togive 1.2 g of compound 22 in 58% yield; mp 115° C.; ¹H NMR δ0.32 (9H,s), 3.94 (3H, s), 3.99 (3H, s), 7.03 (1H, s), 7.88 (1H, s); ¹³C NMRδ-7.2, 56.7, 107.7, 117.3, 134.0, 146.8, 149.8, 154.1; HRMS calcd forC₁₁H₁₇NO₄Sn—CH₃: 329.9937; found: 329.9939.

Example 3 2,3-Methylenedioxy-8,9-dimethoxybenzo[i]phenanthridine (6)

Using a procedure similar to that described in Example 1, exceptreplacing the compound 17 used therein with compound 18, the titlecompound was prepared in 60% yield; mp>250° C.; IR (Nujol) 1680; UV(CHCl₃) 285, 360, 380 nm (log ε=3.01, 2.21, 2.47); ¹H NMR δ4.10 (3H, s),4.14 (3H, s), 6.15 (2H, s), 7.28 (1H, s), 7.68 (1H, s), 7.83 (1H, s),7.97 (1H, d, J=9.2), 8.16 (1H, s), 8.28 (1H, d, J=9.2), 9.85 (1H, s);¹³C NMR δ56.7, 100.3, 102.1, 102.2, 106.1, 109.2, 118.4, 127.5, 128.9,131.2, 131.7, 140.8, 145.6, 145.7, 148.4, 149.9, 150.4, 151.7, 176.1;HRMS calcd for C₂₀H₁₅NO₄: 333.1001; found: 333.0999.

The intermediate compound 18 was prepared as follows.

a. Ethyl-3,4-(methylenedioxy)dihydrocinnamate (19)

Trimethylsilyl chloride 2.5 mL (18.2 mmol) was added to a solution of1.5 g (7.7 mmol) of 3,4-(methylenedioxy)dihydrocinnamic acid in 70 mLdry ethanol and this mixture was stirred at room temperature undernitrogen for 12 h. The excess ethanol was evaporated in vacuo and theresidue obtained was chromatographed on 100 g silica gel using 1:9mixture respectively of ethyl acetate and hexanes to give a quantitativeyield of the ester (19) as a colorless liquid; ¹H NMR δ1.21 (3H, t),2.60 (2H, t), 2.87 (2H, t), 4.08 (2H, q, J=14.1, 7.3), 5.90 (2H, s),6.56-6.69 (3H, m); ¹³C NMR δ14.5, 25.1, 34.2,60.7, 100.8, 106.9, 121.8,122.2, 122.5, 145.3, 147.1, 173.2; HRMS calcd for C₁₂H₁₄O₄: 222.0892;found: 222.0895.

b. 3,4-(Methylenedioxy)phenethylmethylsulfinylmethyl ketone (20)

The anion of dimethyl sulfoxide was prepared by adding 6.0 mL drydimethyl sulfoxide to 600 mg sodium hydride and heating the mixture at70-75° C. for 45 min under nitrogen. This reaction mixture was allowedto cool to room temperature and then transferred to a water bathmaintained at 5-10° C. A solution of compound 19 (1.0 g, 4.54 mmol) in6.0 mL dry dimethyl sulfoxide was added dropwise, over a period of 15min, to the dimethyl sulfoxide anion generated previously. The reactionmixture was slowly allowed to come to room temperature and stirred for 2h. The reaction mixture was poured into 100 mL cold water and acidifiedto pH 3-4 using 1.2 N hydrochloric acid and extracted five times with 40mL portions of chloroform. The combined organic layer was washed twicewith 100 mL portions of distilled water, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to give quantitative yield of20 as a low melting buff colored solid. Compound 20 was found to beunstable to column chromatography using silica gel, however, ¹H NMR ofthe crude compound indicated that it could be used for the synthesis of21 without further purification; mp=60-62° C.; ¹H NMR δ2.55 (3H, s),2.75-2.82 (4H, m), 3.56-3.76 (2H, q, J₁=13.8, J₂=34.3), 5.82 (2H, s),(3H, m); ¹³C NMR δ29.3,41.4,47.4, 64.4, 101.3, 108.7, 109.3, 121.6,134.4, 146.4, 148.1, 202.1.

c. 1,2,3,4-Tetrahydro-1-methylthio-6,7-methylenedioxy-2(1H)-napthalenone(21)

Trifluoroacetic acid (0.3 mL, 3.7 mmol) was dissolved in 25 mL benzeneand added to the reaction flask containing 470 mg (1.85 mmol) ofcompound 20. The reaction mixture was heated to reflux for 1.5 h. Oncooling to room temperature the reaction mixture was transferred to aseparating funnel and washed twice using 10 mL portions of a saturatedsolution of sodium bicarbonate. The benzene layer was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to give a redsyrup which was chromatographed over 100 g of silica gel using 1:9mixture respectively of ethyl acetate and hexanes to give 21 in 60%yield; mp=52° C.; ¹H NMR δ2.05 (3H, s), 2.70-3.10 (4H, m), 4.02 (1H, s),5.85 (1H, s) 6.65 (1H, d, J=8.1), 6.72 (1H, d, J=8.1); ¹³C NMR δ16.3,21.1, 34.2, 54.1, 101.6, 107.9, 118.5, 123.0, 127.6, 145.1, 147.3,203.5; HRMS calcd for C₁₂H₁₂O₃S: 236.0507; found: 236.0505.

d. 6,7-Methylenedioxy-2-tetralone (9)

A solution of 21 (669 mg, 2.83 mmol) in 10 mL glacial acetic acid wasplaced in a hydrogenation flask. To this mixture 460 mg of 10% Pd-C wasadded and the resulting mixture was shaken in a Parr apparatus at 40psig of hydrogen for 40 h. The reaction mixture was filtered through acelite bed, which was washed thrice with 5 mL portions of glacial aceticacid. The glacial acetic acid was rotaevaporated to give the crudetetralone, 9. The crude tetralone was then treated with sodium bisulfiteto convert it to the more stable bisulfite adduct. Pure tetralone wasgenerated as required from its bisulfite adduct by treatment with 10%sodium carbonate solution followed by extraction with dichloromethane;mp=91-92° C. (lit¹⁴⁴=88-91° C.); IR (Nujol) 1727; ¹H NMR δ2.51 (2H, t),2.97(2H, t), 3.48 (2H, s), 5.92 (2H, s), 6.58 (1H, s), 6.69 (1H, s); ¹³CNMR δ21.5, 37.7, 45.1, 101.4, 107.5, 118.5, 121.0, 127.8, 144.2, 146.4,211.5; Anal. calcd for C₁₁H₁₀O₃: C, 69.46; H, 5.30; Found: C, 69.40; H,5.29.

e. 2-Bromo-6,7-methylenedioxy-1-napthaldehyde (11)

Using a procedure similar to that described in Example 1, sub-part a,except replacing the compound 8 used therein with Compound 9, compound11 was prepared in 96% yield; mp=165-166° C.; IR (Nujol) 1680; ¹H NMRδ6.09 (2H, s), 7.05 (1H, s), 7.51 (1H, d, J=8.7), 7.63 (1H, d, J=8.7),8.60 (1H, s), 10.68 (1H, s); ¹³C NMR δ102.1, 102.3, 104.6, 127.4, 129.5,129.6, 130.1, 131.1, 134.6, 148.6, 151.7, 195.5; Anal. calcd forC₁₂H₇O₃Br: C, 51.60; H, 2.51; Found: C, 51.98; H, 2.48.

f. 2-Bromo-6,7-methylenedioxynapthaldehyde-1-ethylacetal (13)

Using a procedure similar to that described in Example 1, sub-part b,except replacing the compound 10 used therein with compound 11, compound13 was prepared in 95% yield; IR (Nujol) 1665, 1617; ¹H NMR δ4.11-4.18(2H, m), 4.36-4.43 (2H, m), 6.03 (2H, s), 6.56 (1H, s), 7.05 (1H, s),7.41-7.48 (2H, m), 7.73 (1H, s); ¹³C NMR δ65.6, 101.8, 102.6, 104.8,106.3, 123.0, 128.0, 129.3, 130.4, 131.1, 131.5, 147.9, 148.6; Anal.calcd for C₁₄H₁₁O₄Br: C, 52.10; H, 3.41; Found: C, 52.52; H, 3.48.

g. 1-Formyl-6,7-methylenedioxynaphth-2-yl boronic acid (15)

Acetal 13 (1.4 mmol) was dissolved in 10 mL anhydrous tetrahydrofuran.This solution was stirred under nitrogen at −78° C. A hexanes solutionof n-butyllithium (1.2 mL, 2.8 mmol) was added slowly and the reactionmixture was stirred at −78° C. for 30 min. A pale yellowish brownsolution was obtained. To this yellow reaction mixture trimethylborate(0.5 mL, 4.2 mmol) was added and the resulting mixture was stirred at−78° C. for 1 h prior to allowing it to come to room temperature. A 5%solution of hydrochloric acid (20 mL) was added to the reaction mixtureand stirred for 30 min at room temperature. The tetrahydrofuran wasevaporated in vacuo and the water layer was extracted withdichloromethane. The combined organic layer was washed once with brine,dried and evaporated to give the boronic acid derivative 15, which wasused in the subsequent step without further purification.

h. 2-(3,4-Dimethoxy-6-nitrophenyl)-6,7-methylenedioxy-1-naphthaldehyde(18)

Using a procedure similar to that described in Example 1, sub-part d,except replacing the compound 14 used therein with compound 15, compound18 was prepared in 25% yield; mp=225° C.; IR (Nujol) 1670, 1515, 1309;¹H NMR δ3.92 (3H, s), 4.04 (3H, s), 6.13 (2H, s), 6.74 (1H, s), 7.13(1H, d, J=8.3), 7.18 (1H, s), 7.77 (1H, s), 7.87 (1H, d,J=8.3), 8.76(1H, s), 10.14 (1H, s); ¹³C NMR δ57.0, 57.1, 102.1, 103.1, 104.7, 108.2,114.9, 125.7, 127.9, 128.8, 129.5, 131.5, 133.6, 141.2, 144.1, 148.6,149.2, 151.6, 152.9, 193.6.

Example 48,9-Dimethoxy-5-methyl-2,3-methylenedioxybenzo[i]-phenanthridine (7)

Using a procedure similar to that described in Example 1, exceptreplacing the compound 17 used therein with compound 26, the titlecompound was prepared in 63% yield; mp>250° C.; IR (Nujol) 1685; UV(CHCl₃) 280, 365, 385 nm (log ε=2.79, 1.90, 2.03); ¹H NMR δ3.36 (3H, s),4.08 (3H, s), 4.13 (3H, s), 6.15 (2H, s), 7.31 (1H, s), 7.51 (1H, s),7.80 (1H, s), 7.93 (1H, d, J=9.1), 8.29-8.35 (2H, m); ¹³C NMR δ31.7,56.6, 102.1, 105.8, 106.3, 108.8, 118.5, 119.1, 122.9, 127.9, 130.2,131.3, 132.7, 137.1, 140.3, 147.3, 148.8, 149.7, 151.7, 155.2; HRMScalcd for C₂₁H₁₇NO₄: 347.1158; found: 347.1156.

The intermediate compound 26 was prepared as follows.

a. 1-Aceto-2-bromo-6,7-methylenedioxynapthalene (24)

Using a procedure similar to that described in Example 3, sub-part a,except replacing the compound 10 used therein with compound 11, compound24 was prepared in 90% yield; mp=138° C.; IR (Nujol) 1695; ¹H NMR δ2.67(3H, s), 6.06 (2H, s), 6.89 (1 H, s), 7.09 (1H, s), 7.41 (1H, d, J=8.8),7.56 (1H, d, J=8.8); ¹³C NMR δ32.4, 101.0, 102.1, 104.9, 113.6, 127.6,128.4, 129.6, 130.1, 139.8, 148.6, 149.7, 205.2; HRMS calcd forC₁₃H₉O₃Br: 291.9735; found: 291.9730.

b. 1-Aceto-2-(3,4-dimethoxy-6-nitrophenyl)-6,7-methylenedioxy-napthalene(26)

Using a procedure similar to that described in Example 3, sub-part b,except replacing the compound 23 used therein with compound 24, compound26 was prepared in 20% yield; mp=190-192° C.; IR (Nujol) 1680, 1523,1300; ¹H NMR δ2.23 (3H, s), 3.89 (3H, s), 4.01 (3H, s), 6.07 (2H, s),6.75 (1H, s), 7.06 (1H, d, J=8.4), 7.10 (1H, s), 7.16 (1H, s), 7.66 (2H,m); ¹³C NMR δ32.6, 56.9, 57.1, 101.7, 102.6, 105.0, 108.4, 115.6, 125.1,126.0, 128.7, 129.5, 130.8, 131.5, 133.8, 144.5, 149.6, 150.5, 150.7,152.8, 207.6.

Example 5 2,3-Dimethoxy-9-benzyloxybenzo[i]phenanthridine (30)

2-( 4-Benzyloxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (100 mg,0.23 mmol) was dissolved in glacial acetic acid (15 mL) and heated toreflux with zinc dust (163 mg, 2.5 mmol) for 3.5 h. Acetic acid wasevaporated in vacuo and the residue was dissolved in chloroform. Thesolution was filtered through a celite bed and the filtrate was washedsuccessively with saturated sodium bicarbonate solution and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was chromatographed over 50 g of silicagel using 1:2 mixture respectively of hexanes and ethyl acetate to givethe title compound as a white solid in 56% yield; ¹H NMR(CDCl₃)δ4.08(3H, s), 4.18(3H, s), 5.29(2H, s), 7.33(1H, s), 7.42(5H, m),7.52(1H, d, J=8.9), 7.72(1H, d, J=2.6), 8.02(1H, d, J=8.9), 8.17(1H, s),8.39(1H, d, J=8.9), 8.52(1H, d, J=8.9), 10.04(1H, s); ¹³C NMR(CDCl₃)δ56.5, 56.6,70.8, 102.3, 108.6, 110.9, 112.8, 118.4, 119.6, 120.7,124.2, 125.8, 127.7, 128.2, 128.6, 129.2, 131.4, 131.7, 137.1, 146.8,148.6, 150.1, 151.2, 159.5; HRMS calcd for C₂₆H₂₄N₃: 395.1521 , found:395.1522.

The intermediate nitroaldehyde was prepared as follows.

a. 2-Bromo-3,4-dihydro-6,7-dimethoxy-1-napthaldehyde

Dimethylformamide (1.6 ml , 20 mmol) was added dropwise to a solution ofphosphorus tribromide (1.6 ml, 17 mmol) in dry chloroform (25 ml) at 0°C. The mixture was stirred at 0° C. for 1 h to give pale yellowsuspension. A solution of 6,7-Dimethoxy-2-tetralone (1.0 g, 4.9 mmol) indry chloroform(20 ml) was added to the yellow suspension and the mixturewas heated at reflux for 1 h. The reaction mixture was cooled to 0° C.and saturated aqueous NaHCO, solution was added dropwise until noeffervescence was obtained. The resulting mixture was extracted withdichloromethane, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was chromatographed over 100 g ofsilica gel using 3:1 mixture respectively of hexanes and ethyl acetateto give the bromoaldehyde in 80% yield; ¹H NMR(CDCl₃) δ2.83(2H, t,J=8.0), 3.88(3H, s), 3.89(3H, s), 6.66(1H, s), 7.71(1H, s), 10.31(1H,s); ¹³C NMR(CDCl₃) δ28.9, 38.5, 56.4,56.5, 110.0, 111.1, 123.0, 128.0,132.7, 144.2, 147.7, 149.1, 193.6.

b. 2-Bromo-6,7-dimethoxy-1-napthaldehyde

2-Bromo-3,4-dihydro-6,7-dimethoxy-1-napthaldehyde (960 mg, 3.23 mmol)and DDQ (880 mg, 3.88 mmol) was refluxed in toluene(45 mL) for 12 h.After cooling to room temperature, the mixture was subjected tofiltration through a celite bed and the filtrate was evaporated todryness. The residue obtained was chromatographed on 100 g silica gelusing 3:1 mixture respectively of hexanes and ethyl acetate to give thearomatic compound in 95% yield; IR(KBr) 1671; ¹H NMR(CDCl₃) δ4.00(3H,s), 4.05(3H, s), 7.07(1H, s), 7.54(1H, d, J=8.5), 7.79(1H, d, J=8.5),8.71(1H, s) 10.74(1H, s); ¹³C NMR(CDCl₃) δ56.3, 56.6, 104.2, 107.0,126.5, 128.8, 129.4, 129.8, 129.9, 134.3, 150.4, 153.1, 195.9; HRMScalcd for C₁₃H₁₁O₃Br: 993.9891; found: 293.9896.

c. 4-Bromo-3-nitrophenol

4-Bromo-3-nitroanisole (2.32g, 10 mmol) was dissolved in 25 mLdichloromethane and cooled in an acetone-dry ice bath at −78° C. undernitrogen. A solution of BBr₃ (1.0M in dichloromethane) (25 mL, 25 mmol)was added dropwise. Gradually increased temperature to 20° C., stirredfor 30 h. The reaction mixture was cooled to 0° C. and distilled water(30 mL) was added dropwise. The aqueous layer was extracted with ethylacetate (30 mL×2) . The combined organic layer was washed successivelywith saturated NaHCO, solution (30 mL×2). The organic layer was driedover anhydrous sodium sulfate, filtered and evaporated in vacuo. Theresidue was chromatographed over 100 g of silica gel using 3:1 mixturerespectively of hexanes and ethyl acetate to give the phenol in 70%yield; ¹H NMR(CDCl₃) δ6.92(1H, dd, J₁=2.9, J₂=8.8), 7.36(1H, d, J=2.9),7.56(1H, d, J=8.8); ¹³C NMR(CDCl₃) δ105.2 113.4, 116.4, 121.4, 136.3,155.9; HRMS calcd for C₆H₄NO₃Br: 216.9374, found: 216.9375.

d. 5-Benzyloxy-2-bromonitrobenzene

A solution of 4-Bromo-3-nitrophenol (1.0 g, 4.6 mmol) and benzyl bromide(0.82 mL, 7 mmol) in acetonitrile (30 mL) and acetone (15 mL) wastreated with K₂CO₃ (970 mg, 7 mmol). The resulting mixture was heated atreflux under nitrogen for 17 h. The reaction mixture was evaporated invacuo and the residue was dissolved in 40 mL ethyl acetate. The solutionwas filtered under vacuum then the filtrate was washed successively withdistilled water (30 mL ), 1M HCl solution (30 mL×3), brine (30 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was chromatographed over 100 g ofsilica gel using 3:1 mixture respectively of hexanes and ethyl acetateto give the benzyl alcohol in 95% yield; ¹H NMR(CDCl₃) δ5.11(2H, s),7.02(1 H, dd, J₁=2.9, J₂=8.9), 7.41(5H, m), 7.46(1 H, d, J=2.9),7.60(1H, d, J=8.9); ¹³C NMR(CDCl₃) δ71.4, 105.4, 112.4, 121.1, 128.1,128.9, 129.1, 129.3, 129.5, 135.8, 136.0, 138.2, 158.7; HRMS calcd forC₁₃H₁₀NO₃Br: 306.9844; found: 306.9846.

e. 4-Benzyloxy-2-nitrophenyl-trimethylstannane

A mixture of hexmethylditin (1.0 g, 3 mmol),5-Benzyloxy-2-bromonitrobenzene (462 mg, 1.5 mmol) and Pd(PPh₃), (70 mg)in anhydrous THF (25 ml) was heated to reflux under nitrogen for 18 h.After cooling to room temperature, THF was evaporated and methylenechloride (30 ml) was added to the residue. To this mixture, potasiumfluoride solution (7M, 2 ml) was added dropwise with vigorous stirring.The mixture was passed through a celite bed and the filtrate was washedwith brine. The methylene chloride layer was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed over 100 g of silica gel using 6:1 mixture respectivelyof hexanes and ethyl acetate to give the stannane in 70% yield; ¹HNMR(CDCl₃) δ0.32 (9H, s), 5.16(2H, s), 7.24(1H, dd, J₁=2.5, J₂=8.1),7.42(5H, m), 7.56(1H, d, J=8.1), 7.95(1H, d, J=2.5); ¹³C NMR(CDCl₃)δ−7.3, 70.9, 110.4, 121.8, 128.0, 128.8, 129.2, 130.7, 136.4, 138.2.154.6, 160.3.

f. 2-(4-Benzyloxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde

Pd(PPh₃)₄ (60 mg, 0.07 mmol) and CuBr (10 mg, 0.07 mmol) was added to asolution of compound 2-bromo-6,7-dimethoxy-1-napthaldehyde (204 mg, 0.69mmol) and 4-benzyloxy-2-nitrophenyl-trimethylstannane (320 mg, 0.82mmol) in THF(20 mL). The resulted mixture was refluxed under nitrogenfor 6 h. After cooling to room temperature, THF was evaporated and ethylacetate (30 mL) was added to the residue. The resulting solution waswashed with distilled water (20 mL). The two phases was separated asmuch as possible and the aqueous layer was discarded. The remaining waspassed through a celite bed. Seperated organic layer was washed withbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo. The residue was chromatographed over75 g of silica gel using 3:1 mixture respectively of hexanes and ethylacetate to give the nitroaldehyde as light yellow solid in 92% yield; ¹HNMR(CDCl₃) δ4.05(3H, s), 4.09(3H, s), 5.21(2H, s), 7.12(1H, d, J=8.3),7.18(1H, s), 7.28(1H, d, J=2.3), 7.30(1H, s), 7.45(5H, m), 7.72(1H, d,J=2.3), 7.88(1H, d, J=8.3), 8.86(1H, s), 10.18(1H, s); ¹³C NMR(CDCl₃)δ56.3, 56.6,71.4, 105.2, 107.1, 110.9, 114.1, 120.0, 123.9, 125.8,126.4, 127.1, 127.4, 128.1, 129.0, 129.4, 130.3, 133.2, 134.7, 135.9,150.3, 150.9, 168.8, 193.9; HRMS calcd for C₂₆H₂₁NO₆: 443.1369, found:443.1370.

Example 6 2,3-Dimethoxy-9-aminobenzo[i]phenanthridine (31)

2-(4,6-Dinitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (100 mg, 0.26 mmol)was dissolved in glacial acetic acid (15 mL) and heated to reflux withzinc dust (180 mg, 2.7 mmol) for 3 h. Acetic acid was evaporated invacuo and the residue was dissolved in chloroform. The solution wasfiltered through a celite bed and the filtrate was washed successivelywith saturated sodium bicarbonate solution and brine. The organic layerwas dried over anhydrous sodium sulfate, filtered and evaporated invacuo. The residue was chromatographed over 50 g of silica gel using 8:1mixture respectively of ethyl acetate and methanol to give the titlecompound as an orange-yellow solid in 30% yield; ¹H NMR(CD₃OD) δ3.95(3H,s), 4.04(3H, s), 7.12(1H, dd, J₁=8.8, J₂=2.3), 7.22(1H, d, J=2.3),7.26(1H, s), 7.86(1H, d, J=9.0), 7.98(1H, s), 8.17(1H, d, J=9.0),8.29(1H, d, J=8.8), 9.68(1H, s); ¹³C NMR(CD₃OD) δ59.3, 59.5, 105.0,112.4, 112.9, 120.9, 121.4, 122.6, 123.2, 127.7,129.7, 131.2, 135.7,136.2, 149.5, 151.3, 153.5, 153.7, 155.1; HRMS calcd for C₁₉H₁₆N₂O₂:304.1212, found: 304.1212.

The intermediate nitro aldehyde was prepared as follows.

a. 2,4-Dinitro-trimethylstannane

A mixture of hexmethylditin (1.0 g, 3.0 mmol), and2,4-dinitroiodobenzene (588 mg, 2.0 mmol) and Pd(PPh₃)₄ (95 mg) inanhydrous THF (25 ml) was heated to reflux under nitrogen for 18 h.After cooling to room temperature, THF was evaporated and methylenechloride (30 ml) was added to the residue. To this mixture, potasiumfluoride solution (7M, 2 ml) was added dropwise with vigorous stirring.The mixture was passed through a celite bed and the filtrate was washedwith brine. The methylene chloride layer was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed over 100 g of silica gel using 6:1 mixture respectivelyof hexanes and ethyl acetate to give the stannane as shining yellowcrystals in 53% yield; ¹H NMR(CDCl₃) δ0.43(9H, s), 7.93(1 H, d, J=8.0),8.42(1H, dd, J₁=8.0, J₂=2.1), 9.11(1H, d, J=2.1); ¹³C NMR(CDCl₃) δ−6.9,119.2, 127.2, 139.0, 149.4, 150.0, 154.1; HRMS calcd for CH₉N₁₂O₄Sn—CH:316.9584; found: 316.9584.

b. 2-(4,6-Dinitrophenyl)-6,7-dimethoxy-1-naphthaldehyde

Pd(PPh₃)₄ (60 mg, 0.07 mmol) and CuBr (10 mg, 0.07 mmol) was added to asolution of compound 2-Bromo-6,7-dimethoxy-1-napthaldehyde (186 mg, 0.63mmol) and compound 2,4-dinitrotrimethylstannane (250 mg, 0.76 mmol) inTHF(20 mL). The resulted mixture was refluxed under nitrogen for 6 h.After cooling to room temperature, THF was evaporated and ethyl acetate(30 mL) was added to the residue. The resulting solution was washed withdistilled water (20 mL). The two phases was seperated as much aspossible and the aqueous layer was discarded. The remaining was passedthrough a celite bed. Seperated organic layer was washed with brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was chromatographed over 75 g of silicagel using 3:1 mixture respectively of hexanes and ethyl acetate to givethe nitroaldehyde as yellow solid in 95% yield; ¹H NMR(CDCl₃) δ4.06(3H,s), 4.10(3H, s), 7.10(1H, d, J=8.3), 7.22(1H, s), 7.64(1H, d, J=8.3),7.95(1H, J=8.3), 8.50(1H, dd, J₁=8.3, J₂=2.3), 8.63(1H, s), 8.96(1H, d,J=2.3), 10.30(1H, s); ¹³C NMR(CDCl₃) δ56.4, 56.7, 104.3, 107.1, 120.5,124.5, 126.9, 128.0, 131.0, 133.4, 134.7, 139.3, 142.2, 148.0, 149.3,151.0, 153.4, 191.9; HRMS calcd for C₁₉ H₁₄N₂O₇: 382.0801, found:382.0801.

Example 7 2,3,8,9-Dimethylenedioxybenzo[i]phenanthridine (29)

Compound2-(3,4-methylenedioxy-6-nitophenyl)-6,7-methylenedioxy-1-naphthaldehyde(100 mg, 0.30 mmol) was dissolved in glacial acetic acid (20 mL) andheated to reflux with znic dust (200 mg, 3.2 mmol) for 3 h. Acetic acidwas evaporated in vacuo and the residue was dissolved in chloroform. Thesolution was filtered through a celite bed and the filtrate was washedsuccessively with saturated sodium bicarbonate solution and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was chromatographed over 75 g of silicagel using 1:1 mixture respectively of hexanes and ethyl acetate to givethe title compound in 40% yield; ¹H NMR(CDCl₃) δ6.17(2H, s), 6.18(2H,s), 7.31(1H, s), 7.58(1H, s), 7.92(1H, s), 7.96(1H, d, J=9.2), 8.20(1H,s), 8.25(1H, d, J=9.2), 9.88(1H, s); ¹³C NMR(CDCl₃) δ99.8, 100.4, 102.1,102.3, 106.2, 107.7, 118.8, 123.9, 127.0, 127.9, 130.9, 131.3, 146.2,148.3, 149.7, 151.3, 152.0, 152.9, 154.4; HRMS calcd for C₁₉H₁₄NO₄:317.0688, found: 317.0688.

The intermediate nitro aldehyde was prepared as follows.

a. 3-(3,4-Methylenedioxyphenyl) propionyl chloride

3-(3,4-Methylenedioxyphenyl) propionic acid (600 mg, 3.0 mmol) wassuspended in methylene chloride (10 ml) and catalytic amount of pyridine(1 drop) was added. Thionyl chloride (0.27 ml, 3.6 mmol) was then addeddropwise and the reaction mixture was stirred vigorously under nitrogenat room temperature for 20 h. After reaction was completed(monitored byTLC), reaction mixture was evaporated in vacuo to give a quantitativeyield of the acid chloride as a yellow oil which was used withoutfurther purifications. ¹H NMR(CDCl₃) δ2.93(2H, t, J=7.3), 3.16(2H, t,J=7.3), 5.94(2H, s), 6.63(1H, d, J=7.7), 6.68(1H,s), 6.73(1H, d, J=7.7);¹³C NMR(CDCl₃) δ31.3, 40.3, 101.5, 108.9, 109.2, 121.8, 132.8, 146.9148.3 173.5.

b. 1-[2-(Diazomethylcarbonyl)ethyl]-3,4-methylenedioxybenzene

To a solution of TMSCHN₂ (3 ml, 6 mmol, 2M in hexane) in 5 mlTHF-acetonitrile (1:1) was added dropwise a solution of compound3-(3,4-Methylenedioxyphenyl)-propionyl chloride (600 mg, 3 mmol) in 5 mlTHF-acetonitrile (1:1) at 0° C. The resulted mixture was stirred at 0°C. for 4 h. After reaction was completed, reaction mixture wasevaporated in vacuo to give the diazo compound as a red viscous oil in95% yield which was used without further purifications.

c. 6,7-Methylenedioxy-2-tetralone

To a solution of rhodium(II) acetate in dichloromethane (15 ml) wasadded dropwise a dichloromethane solution of compound1-[2-(diazomethylcarbonyl)ethyl]-3,4-methylenedioxybenzene. The resultedmixture was refluxed under nitrogen for 1 h. Then the reaction mixturewas evaporated in vacuo to give the tetralone as deep yellow crystals in90% yield which was used without further purifications. mp=91-92° C.;IR(Nujol) 1727; ¹H NMR(CDCl₃) δ2.52(2H, t, J=6.9), 2.96(2H, t, J=6.9),3.48(2H, s),5.93(2H, s), 6.60(1H, s), 6.71(1H, s); ¹³C NMR(CDCl₃) δ28.7,38.7, 45.4, 101.4, 108.7, 108.9, 121.7, 126.6, 130.3, 147.0, 210.9; Analcalcd for C₁₁H₁₆O₃: C, 69.46; H, 5.30; found: C, 69.40; H, 5.29.

d. 2-Bromo-3,4-dihydro-6,7-methylenedioxy-1-napthaldehyde

Dimethylformamide (0.8 ml, 10 mmol) was added dropwise to a solution ofphosphorus tribromide (0.8 ml, 8.5 mmol) in dry chloroform (20 ml) at 0°C. The mixture was stirred at 0° C. for 1 h to give pale yellowsuspension. A solution of compound 6,7-methylenedioxy-2-tetralone (500mg, 2.6 mmol) in dry chloroform(20 ml) was added to the yellowsuspension and the mixture was heated at reflux for 1 h. The reactionmixture was cooled to 0° C. and saturated aqueous NaHCO₃ solution wasadded dropwise until no effervescence was obtained. The resultingmixture was extracted with dichloromethane, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed over 100 g of silica gel using 3:1 mixture respectivelyof hexanes and ethyl acetate to give the aldehyde in 60% yield; ¹HNMR(CDCl₃) δ2.80(2H, t, J=7.8), 2.98(2H, t, J=7.8), 5.93(2H, s),6.64(1H, s), 7.57(1H, s), 10.28(1H, s); ¹³C NMR(CDCl₃) δ29.3, 30.4,101.6, 107.3,108.6, 124.0, 129.7, 132.7, 114.0, 146.7, 147.7, 193.2.

e. 2-Bromo-6,7-methylenedioxy-1-napthaldehyde

2-Bromo-3,4-dihydro-6,7-methylenedioxy-1-napthaldehyde (160 mg, 0.57mmol) and DDQ (154 mg, 0.68 mmol) was refluxed in toluene(20 mL) for 12h. After cooling to room temperature, the mixture was subjected tofiltration through a celite bed and the filtrate was evaporated todryness. The residue obtained was chromatographed on 75 g silica gelusing 3:1 mixture respectively of hexanes and ethyl acetate to give thearomatic aldehyde in 90% yield; ¹H NMR(CDCl₃) δ6.11(2H, s), 7.10(1H, s),7.53 (1H, d, J=8.5), 7.67(1H, d, J=8.5), 8.65(1H, s), 10.73(1H, s); ¹³CNMR (CDCl₃)δ102.1, 102.3, 104.7, 127.4, 129.5, 129.7, 130.2, 131.2,134.7, 148.6, 151.7, 195.6; Anal. calcd for C₁₂H₇O₃Br: C, 51.60; H,2.51; found: C, 51.98; H, 2.48.

f.2-(3,4-Methylenedioxy-6-nitophenyl)-6,7-methylenedioxy-1-naphthaldehyde

Pd(PPh₃)₄ (60 mg) and CuBr (10 mg) was added to a solution of compound2-Bromo-6,7-methylenedioxy-1-napthaldehyde (176 mg, 0.63 mmol) andcompound 3,4-methylenedioxy-6-nitrophenyl-trimethylstannane (251 mg,0.76 mmol) in THF(20 mL). The resulted mixture was refluxed undernitrogen for 12 h. After cooling to room temperature, THF was evaporatedand ethyl acetate (30 mL) was added to the residue. The resultingsolution was washed with distilled water (20 mL). The two phases wasseperated as much as possible and the aqueous layer was discarded. Theremaining was passed through a celite bed. Seperated organic layer waswashed with brine. The organic layer was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed over 75 g of silica gel using 3:1 mixture respectivelyof hexanes and ethyl acetate to give the nitroaldehyde in 70% yield; ¹HNMR (CDCl₃) δ6.12(2H,s), 6.21(2H, s), 6.76(1H, s), 7.09(1H, d, J=8.4),7.18(11H, s), 7.66(11H, s), 7.84(1H, d, J=8.4), 8.74(1H, s), 10.19(1H,s); ¹³C NMR(CDCl₃) δ102.2, 103.0, 103.8, 104.7, 105.9, 112.2, 124.4,125.5, 127.7, 128.8, 131.4, 131.6, 133.7, 143.6, 148.6, 151.7, 156.3,163.5, 193.3.

The intermediate stannane used in sub-part f was prepared as follows.

g. 3,4-Methylenedioxy-2-bromonitrobenzene

3,4-Methylenedioxy-bromobenzene (5 g, 23 mmol) was slowly added to astirred solution of 35ml concentrated nitric acid and 105 ml glacialacetic acid maintained at 10° C. The reaction mixture was stirred at 15°C. for 1 h and then diluted with 200 ml ice cold water. The resultingmixture was extracted twice with 200 ml portions of ether. The combinedorganic phase was dried and evaporated in vacuo to give the crudeproduct. The crude product was recrystallized from ethanol to givebright yellow needle shaped crystals of the nitro compound in 90% yield;mp 87-89° C.; IR(KBr) 1528, 1333; ¹H NMR (CDCl₃) δ6.14(2H,s), 7.12(1H,s), 7.45(1H, s); ¹³C NMR(CDCl₃) δ104.0, 107.0, 109.0,114.3, 146.2,148.0, 152.1; HRMS calcd for C₃H₄BrNO₄: 244.9323; found: 244.9324.

h. 3,4-Methylenedioxy-6-nitrophenyl-trimethylstannane

A mixture of hexmethylditin (3 g, 10 mmol), the compound from sub-part g(1.6 g, 6.9 mmol) and Pd(PPh₃)₄ (200 mg) in anhydrous THF (30 ml) washeated to reflux under nitrogen for 7 h. After cooling to roomtemperature, THF was evaporated and methylene chloride (30 ml) was addedto the residue. To this mixture, potasium fluoride solution (7M, 2 ml)was added dropwise with vigorous stirring. The mixture was passedthrough a celite bed and the filtrate was washed with brine. Themethylene chloride layer was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo. The residue was chromatographed over100 g of silica gel using 6:1 mixture respectively of hexanes and ethylacetate to give the stannane in 60% yield; ¹H NMR(CDCl₃) δ0.32(9H,s),6.12(2H, s), 7.03(1H, s), 7.80(1H, s); ¹³C NMR(CDCl₃) δ−6.9, 103.3,105.9, 114.7, 137.2, 147.9, 149.4, 153.4; HRMS calcd forC₁₀H₁₃NO₄Sn—CH₂: 315.9632, found: 315.9638.

Example 8 2,8,9-Tetramethoxybenzo[i]phenathridine

A mixture of 2-(3,4-dimethoxyphenyl)-6-methoxy-1-naphthaldehyde (46 mg,0.12 mmol) in acetic acid (4 ml) and zinc dust (100 mg, 1.5 mmol) washeated to reflux for 4 h. Acetic acid was evaporated in vacuo and theresidue extacted with chloroform. The chloroform solution was filteredthrough a celite bed. The filtrate was washed successively withsaturated sodium bicarbonate solution and brine and evaporated todryness. The residue obtained was chromatographed on 75 g silica using a1:1 mixture of hexanes:ethyl acetate as eluent to give the titlecompound (27 mg, 68%): mp 207-209° C.; IR (KBr) 1620, 1487, 1215; ¹H NMRCDCl₃) δ4.00 (3H, s) 4.09 (3H, s), 4.14, (3H, s), 7.33 (1H, d, J=2.6),7.40 (1H, dd, J=9.2, 2.6), 7.62 (1H, s), 7.85 (1H,s), 8.03 (1H, d,J=9.0), 8.41 (1H, d, J=9,0), 8.77 (1H, d, J=9.2), 9.99 (1H, s); 13H NMR(CDCl₃) ° 55.3, 56.6, 101.9, 108.8, 110.0, 119.6, 120.8, 121.7, 124.0,125.2, 130.4, 131.3, 133.6, 141.8, 145.9, 150.3, 151.5, 158.8; HRMScalcd for C₂₀H₁₇NO₂+H:320.1287; found 320.1288.

The intermediate nitro aldehyde was prepared as follows.

a. 2-(3,4-Dimethoxy-6-nitrophenyl)-6-methoxy-1-naphthaldehyde

Using a procedure similar to that described in Example 7, sub-part f,except replacing the naphthyl bromide and the stannane used therein withthe requisite compounds, the nitroaldehyde was prepared; mp 158-160° C.;IR (KBr) 1677, 1518, 1328; ¹H NMR (CDCl₃) δ3.92 (3H, s), 3.97 (3H, s),4.05 (3H, s), 6.74 (1H, s), 720 (1H, d, J=2.7), 7.25 (1H, d, J=8.4),7.35 (1H, dd, J=9.2, 2.7), 7.77 (1H, s), 7.94 (1H, d, J=8.4), 9.15 (1H,d, J=9.2), 10.20 (1H, s); ¹³C NMR (CDCl₃) δ55.8, 57.1, 107.0, 108.3,115.0, 122., 126.4, 127.7, 127.9, 128.7, 129.4, 133.5, 135.5, 141.2,143.0, 149.3, 153.0, 158.7, 193.6; HRMS calcd for C₂₀H₁₂NO₆+H:368.1134;found 367.1129.

Example 9 2,3,8-Trimethoxybenzo[i]phenanthridine

A mixture of 2-(4-methoxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde(30 mg, 0.81 mmol) in acetic acid (3 ml) and zinc dust (100 mg, 1.5mmol) was heated to reflux for 3 hours. Acetic acid was evaporated invacuo and the residue extacted with chloroform. The chloroform solutionwas filtered through a celite bed. The filtrate was washed successivelywith saturated sodium bicarbonate solution and brine and evaporated todryness. The residue obtained was chromatographed on 75 g silica using a1:1 mixture of hexanes:ethyl acetate as eluent to give the titlecompound (20 mg, 77%); IR (KBr) 1615, 1518, 1272; ¹H NMR (CDCl₃) δ4.02(3H, s), 4.08 (3H, s), 4.18 (3H, s), 7.33 (1H, s), 7.37 (1H, dd, J=9.1,2.6 Hz), 7.54 (1H, d, J=2.6), 8.05 (1H, d, J=8.7), 8.42 (1H, d, J=8.7),8.56 (1H, d, J=9.1), 10.05 (1H, s); ¹³C NMR δ56.1, 56.5, 56.6, 102.2,108.6, 109.5, 119.0, 119.2, 119.3, 120.6, 124.1, 125.8, 127.6, 131.4,131.7, 146.7, 148.4, 150.1, 151.1, 160.3; HRMS calcd for C₂₄H₁₂NO₃;319.1208; found 319.1209.

The intermediate nitroaldehyde was prepared as follows.

a. 2-(4-Methoxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (23a)

Using a procedure similar to that described in Example 7, sub-part f,except replacing the naphthyl bromide and the stannane used therein withthe requsite compounds, the nitroaldehyde was prepared; mp 200-202° C.;IR (KBr) 1672, 1523, 1256; ¹H NMR (CDCl₃) δ3.96 (3H, s) 4.04 (3H, s),4.09 (3H, s), 7.14 (1H, D, J=8.1), 7.18 (1H, s), 7.20 (1H, s), 7.20 (1H,dd, J=8.3,2.6), 7.32 (1H, d, J=8.3), 7.83 (1H, d, J=2.9), 7.90 (1H, d,J=8.1), 8.87 (1H, s), 10.17 (1H, s); ¹³C NMR (CDCl₃) δ56.3, 56.6, 106.2,107.0, 109.8, 119.4, 1125.9, 126.8, 127.5, 130.3, 133.2, 134.7, 143.9,149.8, 150.4, 153.1, 160.4, 194.0; HRMS calcd for C₂₀H₁₇NO₆: 367.1056;found 367.1050.

Example 10 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine

A mixture of2-(3,4-methylenedioxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (46mg, 0.12 mmol) in acetic acid (3 mL) and zinc dust (100 mg, 1.5 mmol)was heated to reflux for 3 hours. Acetic acid was evaporated in vacuoand the residue extacted with chloroform. The chloroform solution wasfiltered through a celite bed. The filtrate was washed successively withsaturated sodium bicarbonate solution and brine and evaporated todryness. The residue obtained was chromatographed on 75 g silica using a1:1 mixture of hexanes:ethyl acetate as eluent to give the titlecompound (32 mg, 80%); mp 171-171° C. IR (KBr) 1610, 1461, 1277; 1H NMR(CDCl₃), δ4.06 (3H, s), 4.15 (3H, s), 6.15 (2H, s) 7.27 (11, s). 7.54(1H, s), 7.85(11H, s), 7.94 (1H, d, J=8.7), 8.09(1H, s), 8.15 (1H, d,J=8.7), 9.88 (1H, s); ¹³C NMR (CDCl₃) δ56.4, 56.6, 99.7, 102.3, 102.4,107.7, 108.5, 118.5, 21.0, 121.2, 125.6, 127.7, 130.8, 131.2, 142.8,145.9, 148.8, 149.7, 150.1; HRMS calcd for C₂₀H₁₅NO₄+H; 334,.1079.

The intermediate nitroaldehyde was prepared as follows.

a. 2-(3,4-Methylenedioxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde

Using a procedure similar to that described in Example 7, sub-part f,except replacing the naphthyl bromide and the stannane used therein withthe requsite compounds, the nitroaldehyde was prepared; mp 223-225° C.;IR (KBr) 1677, 1502, 1956; ¹H NMR (CDCl₃) δ(3H, s), 4.09 (3H, s), 6.21(2H, s), 6.78 (1H, s), 7.13 (1H, d, J=8.4), 7.18 (1H, s), 7.66 (1H, s),7.91 (1H, d, J=8.4), 8.84 (1H, s), 10.22 (1H, s); ¹³C NMR (CDCl₃) δ56.3,56.6, 103.9, 105.2, 107.1, 112.3, 125.4, 127.0, 127.5, 130.4, 131.6,133.3, 143.8, 148.5, 150.1, 151.7, 153.1, 193.6,; HRMS calcd forC20H15NO7+H: 382.0927; found 382.0927

For sub-part a of Examples 8-10, the requsite intermediate naphthylbromide can be prepared from commercially avaliable starting materialsusing a sequence similar to that described in Example 7, sub-parts a-d;and the requsite intermediate stannane can be prepared from commerciallyavailable starting materials using a sequence similar to thar describedin Example 7, sub-parts g and h.

Example 11

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet ‘Compound X’ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodiumhydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injectionq.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml ‘Compound X’ (free acidform) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1Polyethylene glycol 400 200.0 01 N Sodium hydroxide solution q.s. (pHadjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosolmg/can ‘Compound X’ 20.0 Oleic acid 10.0 Trichloromonofluoromethane5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein R₁, R₂ and R₃ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₁ and R₂ taken together are methylenedioxy and R₃is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(K), OR_(m), or halo; or R₂ and R₃ takentogether are methylenedioxy and R₁ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; R₄ is oxy, (C₁-C₆)alkyl, or is absent; R₅ is hydrogen,hydroxy, or (C₁-C₆)alkyl; R₆, R₇ and R₈ are each individually hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy,NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₆ and R₇ taken together aremethylenedioxy and R₈ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo;or R₇ and R₈ taken together are methylenedioxy and R₆ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy,NR_(g)R_(h), C(═O)R_(k), COOR_(k), OR_(m), or halo; each bondrepresented by ————— is individually present or absent; X isC(R_(a))(R_(b)) or NR_(c); Y is C(R_(d))(R_(e)) or NR_(f); if present,R_(a) and R_(b) are each independently hydrogen or (C₁-C₆)alkyl if thebond between the 11- and 12-positions represented by ————— is absent; orR_(a) is hydrogen or (C₁-C₆)alkyl and R_(a) is absent if the bondbetween the 11- and 12-positions represented by ————— is present; ifpresent, R_(c) and R_(f) are each independently hydrogen or (C₁-C₆)alkylif the bond between the 11- and 12-positions represented by ————— isabsent; or R_(c) and R_(f) are each independently (C₁-C₆)alkyl or absentif the bond between the 11- and 12-positions represented by ————— ispresent; if present, R_(d) and R_(e) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(d) is hydrogen or (C₁-C₆)alkyl and R_(e) isabsent if the bond between the 11- and 12-positions represented by —————is present; each R_(g) and R_(h) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, aryl,aryl(C₁-C₆)alkyl, aryloxy, or aryl(C₁-C₆)alkoxy; or R_(g) and R_(h)together with the nitrogen to which they are attached are pyrrolidino,piperidino, morpholino, or thiomorpholino; each R_(k) is independentlyhydrogen, or (C₁-C₆)alkyl; and each R_(m) is independently(C₁-C₆)alkanoyl, aryl, or aryl(C₁-C₆)alkyl; wherein any (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, or (C₁-C₆)alkoxy of R¹, R², R³, R⁶, R⁷, R⁸, or R_(k)is optionally substituted on carbon with 1, 2, or 3 substituentsindependently selected from hydroxy, halo, NR_(n)R_(p),(C₃-C₆)cycloalkyl, or (C₁-C₆)alkoxy; wherein each R_(n) and R_(p) isindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy,or (C₁-C₆)alkanoyl; or R_(n) and R_(p) together with the nitrogen towhich they are attached are pyrrolidino, piperidino, morpholino, orthiomorpholino; wherein any aryl is optionally be substituted with 1, 2,or 3 substituents independently selected from hydroxy, halo, nitro,trifluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, and (C₁-C₆)alkoxy; provided that at least one of R₂and R₈ is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro; orat least one of R₂ and R₈ forms part of a methylenedioxy; and providedthat R₁-R₃ and R₆-R₈ are not all hydrogen; provided the compound is not9-methylbenzo[i]phenanthridine;1-chloro-2-methoxybenzo[i]phenanthridine;2-methoxybenzo[i]phenanthridine;2,3-methylenedioxy-8,9-methylenedioxybenzo[i]phenanthridine;5,8-dimethylbenzo[i]phenanthridine;2-methoxy-5-methylbenzo[i]phenanthridine; 2-methoxy-5,8-dimethylbenzo[i]phenanthridine; 5,6-dihydro-9-methylbenzo[i]phenanthridine; or1-chloro-2-methoxy-5,6-dihydrobenzo[i]phenanthridine; or apharmaceutically acceptable salt thereof.
 2. The compound of formula (I)as claimed in claim 1 wherein: R₁, R₂ and R₃ are each individuallyhydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₁ and R₂ takentogether are methylenedioxy and R₃ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₂ and R₃ taken together are methylenedioxy and R₁is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; R₄ is oxy,(C₁-C₆)alkyl, or is absent; R₅ is hydrogen, hydroxy, or (C₁-C₆)alkyl;R₆, R₇ and R₈ are each individually hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(h), COOR_(k),OR_(m), or halo; or R₆ and R₇ taken together are methylenedioxfand R₈ ishydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro,hydroxy, NR_(g)R_(h), COOR_(k), OR_(m), or halo; or R₇ and R₈ takentogether are methylenedioxy and R₆ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, nitro, hydroxy, NR_(g)R_(k), COOR_(k),OR_(m), or halo; each bond represented by ————— is individually presentor absent; X is C(R_(a))(R_(b)) or NR_(c); Y is C(R_(d)(R_(e)) orNR_(f); if present, R_(a) and R_(b) are each independently hydrogen or(C₁-C₆)alkyl if the bond between the 11- and 12-positions represented by————— is absent; or R_(a) is hydrogen or (C₁-C₆)alkyl and R_(b) isabsent if the bond between the 11- and 12-positions represented by —————is present; if present, R_(c) and R_(f) are each independently hydrogenor (C₁-C₆)alkyl if the bond between the 11- and 12-positions representedby ————— is absent; or R_(c) and R_(f) are each independently(C₁-C₆)alkyl or absent if the bond between the 11- and 12-positionsrepresented by ————— is present; if present, R_(d) and R_(e) are eachindependently hydrogen or (C₁-C₆)alkyl if the bond between the 11- and12-positions represented by ————— is absent; or R_(d) is hydrogen or(C₁-C₆)alkyl and R_(e) is absent if the bond between the 11- and12-positions represented by ————— is present; each R_(g) and R_(h) isindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, aryl, aryl(C₁-C₆)alkyl, aryloxy, or aryl(C₁-C₆)alkoxy;or R_(g) and R_(h) together with the nitrogen to which they are attachedare pyrrolidino, piperidino, morpholino, or thiomorpholino; each R_(k)is independently hydrogen, or (C₁-C₆)alkyl; and each R_(m) isindependently (C₁-C₆)alkanoyl, aryl, or aryl(C₁-C₆)alkyl; wherein anyaryl may optionally be substituted with 1, 2, or 3 substituentsindependently selected from hydroxy, halo, nitro, trifluoromethyl,trifluoromethoxy, carboxy, amino, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or(C₁-C₆)alkoxy; provided that at least one of R₂ and R₈ is hydrogen,methyl, nitro, hydroxy, amino, fluoro or chloro; or at least one of R₂and R₈ forms part of a methylenedioxy; and provided that R₁-R₃ and R₆-R₈are not all hydrogen; or a pharmaceutically acceptable salt thereof. 3.The compound of claim 1 wherein R₃ is hydrogen.
 4. The compound of claim1 wherein R₄ is absent and the bond between the 5- and 6-positionsrepresented by ————— is present.
 5. The compound of claim 1 wherein R₄is (C₁-C₆)alkyl.
 6. The compound of claim 1 wherein R₅ is methyl orhydrogen.
 7. The compound of claim 1 wherein R₁, R₂ and R₃ are eachindividually hydrogen, or (C₁-C₆)alkoxy; or R₁ and R₂ taken together aremethylenedioxy and R₃ is hydrogen or (C₁-C₆)alkoxy.
 8. The compound ofclaim 1 wherein R₇ or R₈ is (C₁-C₆)alkoxy; or R₇ and R₈ taken togetherare methylenedioxy.
 9. The compound of claim 1 wherein R₇ and R₈ takentogether are methylenedioxy.
 10. The compound of claim 1 wherein R₂ ishydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro.
 11. Thecompound of claim 1 wherein R₈ is hydrogen, methyl, nitro, hydroxy,amino, fluoro or chloro.
 12. The compound of claim 1 wherein the bondsrepresented by ————— are both present.
 13. The compound of formula (I)as claimed in of claim 1 which is a compound of formula III:

or a pharmaceutically acceptable salt thereof.
 14. The compound offormula (I) as claimed in of claim 1 which is a compound of formula IV:

or a pharmaceutically acceptable salt thereof.
 15. The compound offormula (I) as claimed in of claim 1 which is a compound of formula (V):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 wherein wherein R₁ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₁and R₂ taken together are methylenedioxy.
 17. The compound of claim 1wherein R₂ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or apharmaceutically acceptable salt thereof.
 18. The compound of claim 1wherein R₃ is (C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₂ and R₃ takentogether are methylenedioxy.
 19. The compound of claim 1 wherein R₈ is(C₁-C₆)alkoxy, nitro, hydroxy or halo; or R₇ and R₈ taken together aremethylenedioxy.
 20. The compound of claim 1 wherein R₇ is (C₁-C₆)alkoxy,nitro, hydroxy, or halo.
 21. The compound of claim 1 wherein R₆ is(C₁-C₆)alkoxy, nitro, hydroxy, or halo; or R₆ and R₇ taken together aremethylenedioxy.
 22. The compound of claim 1 which is2,3-methylenedioxy-8,9-dimethoxybenzo[i]phenanthridine; or apharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1, incombination with a pharmaceutically acceptable diluent or carrier.
 24. Amethod of inhibiting cancer cell growth, comprising administering to amammal afflicted with cancer, an amount of a compound of claim 1,effective to inhibit the growth of said cancer cells.
 25. A method forinhibiting cancer cell growth comprising: contacting said cancer cell invitro or in vivo with an amount of a compound of claim 1, effective toinhibit the growth of said cancer cell.
 26. The compound of claim 1which is 2,3,8 trimethoxybenzo-[I]-phenanthridine, 2,3dimethoxy-9-benzyloxybenzo-[I]-phenanthridine, or 2,3dimethoxy-9-aminobenzo-[I]-phenanthridine, or pharmaceuticallyacceptable salts thereof.